Dual isotope simultaneous imaging to evaluate the effects of intracoronary bone marrow-derived mesenchymal stem cells on perfusion and metabolism in canines with acute myocardial infarction

Stem cell therapy on acute myocardial infarction (AMI) has been performed for over a decade. In the present study, cardiac perfusion, metabolism and function in dogs with AMI treated by intracoronary injection of bone marrow-derived mesenchymal stem cells (MSCs) were evaluated by dual isotope simultaneous acquisition (DISA) of single positron emission computed tomography (SPECT). Dogs (n=12, 20-30 kg) were randomly assigned to two groups: A graft study (n=6) and control group (n=6). Bone marrow mesenchymal aspirate was collected 3 weeks before surgical procedure. Stem cells were induced by 5-azacytidine for differentiation into myocytes. The dog AMI model was produced by blocking the blood stream at 1/3 of the distinct left anterior descending coronary artery for 90 min. For dogs in the grafting group, MSCs were transplanted by intracoronary injection, and for the control group, 0.9% NaCl was injected instead. At 1 and 10 weeks after MSCs were grafted, respectively, SPECT DISA was performed for each dog in the two groups with Tc-99m-SPECT MIBI (925 MBq) and F-18-FDG (222 MBq) for evaluation of myocardial perfusion and metabolism. After the dogs were sacrificed, heart tissue was stained by myocyte-specific antibodies for newborn vessels, troponin T and bromodeoxyuridine (BrdU). Following induction by 5-azacytidine, the morphological features with colony formation, microfilament, as well as atrial granules and positive stainings of a-actinin, myosin and troponin I demonstrated strongly that the MSCs differentiated into myocytes. The number of viable myocardial segments was 10 in the grafting group, which was significantly greater compared with the control group. The ejection fraction of the infarcted left ventricle (LVEF,%) increased from 53.80 +/- 9.58 to 70.00 +/- 7.52 (change, 16.20 +/- 2.93) at 1 and 10 weeks after MSCs engraftment, whilst in the control group, LVEF was 50.50 +/- 8.02 and 56.50 +/- 7.24 (change, 5.50 +/- 2.69), respectively. The LVEF difference was statistically significant (P<0.05) between the graft and control groups. Furthermore, immunostaining of all the myocyte-specific antibodies (for newly born vessels, troponin T and BrdU) was positive. In conclusion, direct intracoronary injection of bone marrow MSCs into injured myocardium in the experimental dog AMI model can significantly improve cardiac function with new vessel formation and myocyte-specific biomarker expression, and in particular, the present study further shows that DISA SPECT can be used for the assessment of stem cell transplantation in the heart.